Chapter 6

• Biotransformation is the metabolic conversion of endogenous and xenobiotic chemicals to more water-soluble compounds.
• Xenobiotic biotransformation is accomplished by a limited number of enzymes with broad substrate specificities.
• Phase I reactions involve hydrolysis, reduction, and oxidation. These reactions expose or introduce a functional group (—OH, —NH2, —SH, or —COOH), and usually result in only a small increase in hydrophilicity.
• Phase II biotransformation reactions include glucuronidation, sulfonation (more commonly called sulfation), acetylation, methylation, and conjugation with glutathione (mercapturic acid synthesis), which usually result in increased hydrophilicity and elimination.

Biotransformation is the metabolic conversion of endogenous and xenobiotic chemicals to more water-soluble compounds. Generally, the physical properties of a xenobiotic are changed from those favoring absorption (lipophilicity) to those favoring excretion in urine or feces (hydrophilicity). An exception to this general rule is the elimination of volatile compounds by exhalation.

Chemical modification of a xenobiotic by biotransformation may alter its biological effects. Some drugs undergo biotransformation to active metabolites that exert their pharmacodynamic or toxic effect. In most cases, however, biotransformation terminates the pharmacologic effects of a drug and lessens the toxicity of xenobiotics. Enzymes catalyzing biotransformation reactions often determine the intensity and duration of action of drugs and play a key role in chemical toxicity and chemical tumorigenesis.

### Basic Properties of Xenobiotic Biotransforming Enzymes

Xenobiotic biotransformation is accomplished by a limited number of enzymes with broad substrate specificities. The synthesis of some of these enzymes is triggered by the xenobiotic (by the process of enzyme induction), but in most cases the enzymes are expressed constitutively (i.e., they are synthesized in the absence of a discernible external stimulus). Although the synthesis of steroid hormones is catalyzed by cytochrome P450 enzymes in steroidogenic tissues, this family of enzymes in the liver converts steroid hormones into water-soluble metabolites to be excreted.

The structure (i.e., amino acid sequence) of a given biotransforming enzyme may differ among individuals, which can give rise to differences in rates of xenobiotic biotransformation. The study of the causes, prevalence, and impact of heritable differences in xenobiotic biotransforming enzymes is known as pharmacogenetics.

### Biotransformation versus Metabolism

The terms biotransformation and metabolism are often used synonymously, particularly when applied to drugs. The term metabolism is often used to describe the total fate of a xenobiotic, which includes absorption, distribution, biotransformation, and elimination. However, metabolism is commonly used to mean biotransformation, which is understandable from the standpoint that the products of xenobiotic biotransformation are known as metabolites. Furthermore, individuals with a genetic enzyme deficiency resulting in impaired xenobiotic biotransformation are described as poor metabolizers rather than poor biotransformers.

### Stereochemical Aspects of Biotransformation

Stereochemical properties influence the interaction between a xenobiotic and its biotransforming enzyme. Many xenobiotics, especially drugs, contain one or more chiral centers and can exist in two mirror-image stereoisomers or enantiomers. The biotransformation of some chiral ...

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